Impact of Electron Transport Chain (ETC) Complex I dysfunction on mitochondrial Ca2+ homeostasis

Complex I (CI), also known as NADH ubiquinone oxidoreductase, is a ubiquitous enzyme involved in the generation of the proton-motive force exploited for ATP synthesis in the mitochondrial respiratory chain. CI is a central player of cellular bioenergetics, it owns a pivotal contribution in controlling cell metabolism, adaptation to hypoxia, and sensitivity to apoptosis. Indeed, defects in CI are not only the primary cause of inherited mitochondrial diseases, but are also present in a broad spectrum of pathological conditions, such as diabetes and cancer. The activity of Complex I is directly linked to a key signal of mitochondrial physiology: mitochondrial Ca2+. Indeed, mitochondrial Ca²⁺ activates three key dehydrogenases of mitochondrial metabolism thereby enhancing the production of NADH. The connection between (Ca2+)mt handling and electron transport chain is further highlighted by the essential role of Ca²⁺/H⁺ exchangers, which couples Ca²⁺ efflux to H⁺ influx across the inner mitochondrial membrane to maintain ion homeostasis. Furthermore, the relationship between Complex I and mitochondrial Ca²⁺ homeostasis is not only functional but also structural by a direct physical interaction between Complex I and the MCU pore forming subunit. The aim of this PhD thesis is to investigate the interplay between CI of the mitochondrial respiratory chain and mitochondrial Ca²⁺ homeostasis. This thesis aims to elucidate how the loss or dysfunction of Complex I affects mitochondrial Ca²⁺ dynamics. In particular, the research focuses on analyzing mitochondrial Ca²⁺ fluxes and assessing changes in the expression levels of key proteins involved in mitochondrial Ca²⁺ uptake and release in the context of Complex I impairment.